Nisin is a bacteriocin, an antimicrobial substance produced by a food grade organism, and is a member of a group of similar substances referred to as lantibiotics (or lanthocins herein) and which among others include subtilin, epidermin, gallidermin and pep 5.
Nisin is produced by Lactococcus lactis subsp. lactis belonging to the Lancefield serological group N [Mattick, A. T. R. and A. Hirsch, 1947 Lancet. 2, 5]. Nisin is a peptide comprised of 34 amino acid residues and contains five ring structures cross-linked by thioether bridges that form lanthionine or B-methyllanthionine. These thioethers result from the condensation of cysteine sulfhydryl groups with dehydro side chains formed from either serine or threonine residues as a result of post-translational modifications of a nisin precursor peptide.
It has been reported that nisin acts as a cationic surface active agent and that its activity can be neutralized by anionic detergents [Ramseier, H. R. 1960 Arch. Mikrobiol, 37, 57], and at a molecular level that nisin acts at the cytoplasmic membrane and inhibits peptidoglycan biosynthesis [Reisinger et al. 1980 Arch. Microbiol. 127, 1871]. The action of nisin against vegetative bacteria is most likely the result of voltage dependent depolarization of the plasma membrane following insertion of the peptide into the lipid bilayer, possibly through the interaction of adjacent nisin molecules to form a transient pore or channel. The molecular properties of nisin and the mechanism of its biosynthesis have been the subject of a recent review [Jung, G. and H. G. Sahl 1991 Nisin and Novel Lantibiotics ESCOM Science Publishers, Leiden].
Nisin is considered to have a narrow spectrum of activity and generally is only active against certain Gram positive bacteria, except when combined with a chelating agent when nisin is surprisingly active against Gram negative bacteria and exhibits enhanced activity against Gram positive bacteria (U.S. Pat. Nos. 5,217,950 and 5,260,271 to Blackburn et al.). Nisin has been used as an antimicrobial food preservative and is accepted as safe by JEFCA and various national authorities regulating the use of food additives including those of the USA, UK and EEC.
Although nisin was shown to be effective in preliminary animal model studies [Mattick, A. T. R. and A. Hirsch, 1947 Lancet. 2:5; Bavin, E. M., et al., 1952 Lancet 1:127; Gowans, J. L., et al. 1952 Brit. J. Pharmacol. 7:438; Hirsch, A. and A. T. R. Mattick, 1949 Lancet ii: 190], nisin was found to be insufficiently useful to be developed therapeutically in human or veterinary medicine.
Clostridium difficile is an anaerobic Gram-positive, spore-forming toxigenic bacillus, infrequently found in significant numbers in the colon of humans. However, because it is refractory to a number of antimicrobial agents and is endemic in hospitals and nursing homes, it can appear when the normal bacterial flora of the colon is suppressed, most often after treatment with broad-spectrum antibacterial agents. Under these circumstances, C. difficile can cause severe diseases, known as antibiotic-associated diarrhea and pseudomembranous colitis. Treatments for these disorders include metronidazole and oral vancomycin. Currently, however, the use of vancomycin is being actively discouraged because, particularly in an oral form, it selects for a new class of highly resistant intestinal organisms, vancomycin-resistant enterococci (VRE), which can cause fatal, untreatable infections at other body sites. Metronidazole is not active against enterococci, so its use may also contribute to selection of VRE in the colon. The relapse rate for C. difficile disease is very high, about 20%; it is thought that this may be related to the formation of spores, which are difficult to eradicate.